College of Engineering, Peking University, Beijing, 100871 China.
College of Engineering, Peking University, Beijing, 100871 China ; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871 China.
Cancer Cell Int. 2014 Oct 12;14(1):98. doi: 10.1186/s12935-014-0098-4. eCollection 2014.
Chemotherapy either before or after surgery is a common breast cancer treatment. Long-term, high dose treatments with chemotherapeutic drugs often result in undesirable side effects, frequent recurrences and resistances to therapy.
The anti-cancer drug, gemcitabine (GEM) was used in combination with pulse power technology with nanosecond pulsed electric fields (nsPEFs) for treatment of human breast cancer cells in vitro. Two strategies include sensitizing mammary tumor cells with GEM before nsPEF treatment or sensitizing cells with nsPEFs before GEM treatment. Breast cancer cell lines MCF-7 and MDA-MB-231 were treated with 250 65 ns-duration pulses and electric fields of 15, 20 or 25 kV/cm before or after treatment with 0.38 μM GEM.
Both cell lines exhibited robust synergism for loss of cell viability 24 h and 48 h after treatment; treatment with GEM before nsPEFs was the preferred order. In clonogenic assays, only MDA-MB-231 cells showed synergism; again GEM before nsPEFs was the preferred order. In apoptosis/necrosis assays with Annexin-V-FITC/propidium iodide 2 h after treatment, both cell lines exhibited apoptosis as a major cell death mechanism, but only MDA-MB-231 cells exhibited modest synergism. However, unlike viability assays, nsPEF treatment before GEM was preferred. MDA-MB-231 cells exhibited much greater levels of necrosis then in MCF-7 cells, which were very low. Synergy was robust and greater when nsPEF treatment was before GEM.
Combination treatments with low GEM concentrations and modest nsPEFs provide enhanced cytotoxicity in two breast cancer cell lines. The treatment order is flexible, although long-term survival and short-term cell death analyses indicated different treatment order preferences. Based on synergism, apoptosis mechanisms for both agents were more similar in MCF-7 than in MDA-MB-231 cells. In contrast, necrosis mechanisms for the two agents were distinctly different in MDA-MB-231, but too low to reliably evaluate in MCF-7 cells. While disease mechanisms in the two cell lines are different based on the differential synergistic response to treatments, combination treatment with GEM and nsPEFs should provide an advantageous therapy for breast cancer ablation in vivo.
化疗无论是在手术前还是手术后，都是一种常见的乳腺癌治疗方法。长期、大剂量的化疗药物治疗常常导致不良的副作用、频繁的复发和对治疗的耐药性。
抗癌药物吉西他滨（GEM）与纳秒脉冲电场（nsPEFs）的脉冲功率技术联合用于体外人乳腺癌细胞的治疗。两种策略包括用 GEM 预处理使乳腺肿瘤细胞敏感，然后用 nsPEF 处理，或者先用 nsPEF 处理，然后用 GEM 处理。乳腺癌细胞系 MCF-7 和 MDA-MB-231 用 250 个 65ns 持续时间的脉冲和 15、20 或 25kV/cm 的电场处理，然后用 0.38μM GEM 处理。
两种细胞系在治疗后 24 小时和 48 小时，细胞活力丧失均表现出强烈的协同作用；nsPEF 预处理 GEM 是首选顺序。在集落形成试验中，只有 MDA-MB-231 细胞表现出协同作用；nsPEF 预处理 GEM 仍然是首选顺序。在治疗后 2 小时用 Annexin-V-FITC/碘化丙啶进行凋亡/坏死检测，两种细胞系均表现出凋亡作为主要的细胞死亡机制，但只有 MDA-MB-231 细胞表现出适度的协同作用。然而，与细胞活力测定不同的是，nsPEF 预处理 GEM 是首选。与 MCF-7 细胞相比，MDA-MB-231 细胞的坏死水平要高得多，而 MCF-7 细胞的坏死水平则非常低。当 nsPEF 治疗先于 GEM 时，协同作用更强。
低浓度 GEM 和适度 nsPEF 的联合治疗在两种乳腺癌细胞系中提供了更强的细胞毒性。虽然长期生存和短期细胞死亡分析表明治疗顺序偏好不同，但治疗顺序是灵活的。基于协同作用，两种药物的凋亡机制在 MCF-7 细胞中比在 MDA-MB-231 细胞中更相似。相比之下，两种药物的坏死机制在 MDA-MB-231 细胞中明显不同，但在 MCF-7 细胞中太低而无法可靠评估。尽管两种细胞系的疾病机制不同，但对治疗的协同反应不同，GEM 和 nsPEF 的联合治疗应为体内乳腺癌消融提供有利的治疗方法。
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